Is TONSL p.Arg238Trp (c.712C>T) pathogenic?

TONSL p.Arg238Trp (c.712C>T) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.1267); Rare (popmax 0.166%, afr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Arg238Trp (c.712C>T)?

TONSL p.Arg238Trp (c.712C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Arg238Trp (c.712C>T) in the general population?

TONSL p.Arg238Trp (c.712C>T) is rare (popmax 0.166%, afr) (gnomAD).

What do computational predictors say about TONSL p.Arg238Trp (c.712C>T)?

AlphaMissense predicts likely benign (score 0.1267) — an in-silico prediction, not a clinical call.

TONSL p.Arg238Trp

c.712C>T · rs149978949 · VCV1020525

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1267 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.166%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1267	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -10.71	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -3.1, phastCons 0.016
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.166% African / African-American · 124/74,700 alleles

Filtering AF 0.142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.133%

Overall 0.029% 463/1,595,458 alleles · rare exomes 351/1,443,096 · genomes 112/152,362 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.166%	602
Remaining individualsnot grpmax-eligible	0.0633%	1,580
Admixed American	0.0591%	1,691
Middle Eastern	0.0499%	2,003
South Asian	0.0321%	3,113
European (non-Finnish)	0.0197%	5,075
East Asian	0.00675%	14,821

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TONSL
Protein: p.Arg238Trp
Coding: c.712C>T
MANE Select: NM_013432
dbSNP: rs149978949
Type: single nucleotide variant
Location: chr8:144442279 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 238: a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp)

Full TONSL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TONSL p.Arg238Gln Uncertain significance ★★ ⚠ same residue
TONSL p.Ala1053Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1065Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1093Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1200Thr Uncertain significance ★★ ⚠ same condition
TONSL p.Ala215Thr Uncertain significance ★★ ⚠ same condition
TONSL p.Ala232Val Uncertain significance ★★ ⚠ same condition
TONSL p.Ala331Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tonsl-p-arg238trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown